Mutations in nuclear-encoded mitochondrial genes or mitochondrial DNA (mtDNA) lead to a plethora of metabolic, cardiovascular and neurodegenerative diseases and are a main culprit in aging. Defects in translation of mitochondria-encoded genes are increasingly recognized as a cause of human mitochondriopathies. Mutations in the human Mitochondrial Optimization Factor 1 (MTO1), a tRNA modifier, were identified in children with infantile hypertrophic cardiomyopathy, lactic acidosis and a respiratory chain defect (MIM 614667). Furthermore, MTO1 mutations were found in patients with either complex IV or combined complex I and IV deficiency.
An MTO1-deficient mouse model was recently generated by gene trap mutagenesis. The systematic phenotypic analysis in the German Mouse Clinic revealed that it mirrors the human phenotype remarkably well: the most prominent signs and symptoms were cardiovascular and included bradycardia and cardiomyopathy. In addition, mutant mice showed a high incidence of arrhythmias during induction and reversal of anaesthesia. The detailed morphological and biochemical workup of murine hearts indicated that the myocardial damage was due to mitochondrial dysfunction, evident in complex I deficiency as well as reduced maximum respiration rate. A direct translational consequence of this mouse model may be to caution against anaesthesia-related cardiac arrhythmias which may be fatal in patients with mutations of the MTO1 gene.
Becker et al., MTO1-Deficient Mouse Model Mirrors the Human Phenotype Showing Complex I Defect and Cardiomyopathy. PLoS ONE 9(12): e114918. doi:10.1371/journal.pone.0114918